Atherosclerosis in the susceptible pigeon has many similarities to human atherosclerosis including the geographical localization of lesions in the vascular tree, altered endothelial and smooth muscle cells, and the progression of lesion development. The pigeon model is unique in that susceptibility to spontaneous aortic atherosclerosis in White Carneau (WC) pigeons is due to a single gene and it follows an autosomal recessive pattern of inheritance uncomplicated by any known risk factors. Human atherosclerosis is a complex, multifactorial disease, in contrast to the pigeon model, which represents a simplest-case system suitable for defining the genetic basis for lesion development. Susceptibility to atherosclerosis in the pigeon resides at the level of the arterial wall and is manifested as lesions at the celiac bifurcation of the aorta. However, the mechanism responsible for lesion development is not known, and no studies have been conducted to identify the gene or gene product responsible. Since aortic smooth muscle cells cultured from these pigeons resemble smooth muscle cells in the lesion area both morphologically and biochemically, they will be used as a convenient, easily extractable source of genetic materials for this study. Pools of differentially expressed genes will be isolated by comparing cDNA produced from mRNA expressed in aortic cell cultures from susceptible WC pigeons with that produced from resistant Show Racer (SR) pigeons through a process called Representational Difference Analysis. This technique enriches for isolated genetic material from differentially expressed mRNA, increasing the probability of finding the genetic difference related to atherosclerosis by decreasing the size of the gene pool which must be examined. Differential expression of candidate genes will be verified by Southern blots against cDNA from both breeds and Northern analyses against mRNA extracted from the cultures. The final test for relevancy of the isolated gene or genes will be Southern blots against genomic DNA from Both breeds. The candidate genes will be cloned and sequenced, and the products or functions deduced from existing genomic databases. [unreadable] [unreadable]